This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This resubmission requests support for a 4-year, 4-site, randomized sham-controlled trial of daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) for the acute treatment of major depression, rTMS has shown an antidepressant effect in 20 small sample randomized controlled comparisons, five separate meta analyses of these studies, and in randomized trials with electroconvulsive therapy. However, the sample sizes of these studies have been small and the rTMS stimulus administered may not have been of an adequate dose in terms of the intensity of stimulation or length of treatment in order to demonstrate an optimal antidepressant effect. Considerable skepticism and many questions remain concerning the ultimate clinical meaningfulness of these studies. Recent scientific evidence and pilot data from our groups support the fact that the antidepressant response to rTMS is dose-dependent. The present protocol uses rTMS parameters that maximize the stimulation duration and intensity within the published safety guidelines to treat 240 unipolar depressed adults with moderate levels of treatment resistance. We will investigate the safety and efficacy of repeated daily left prefrontal 5Hz rTMS at 120% of motor threshold (MT) in a 3 week fixed dose trial. In subjects showing an antidepressant response after 3 weeks, rTMS will be administered for up to 6 weeks to achieve remission of clinical symptoms of depression. Patients who do not remit with the initial fixed dose trial will be administered 1Hz rTMS in an open trial over the right prefrontal cortex. Baseline magnetic resonance images will be used to determine the optimal stimulus intensity by adjusting for individual differences in cortical to skull distances. Safety measures will include the most comprehensive neuropsychological testing and adverse event profile used to date. We will also determine the long-term antidepressant effect of TMS in remitters, using a standardized continuation medication protocol over 6 months. Finally, we will evaluate whether neuroanatomic findings on magnetic resonance images, stimulus location, demographic, and/or clinical variables affect clinical response to TMS. [This clinical site grant (CSG) proposal is one of four scientifically identical proposals resubmitted under a CSMD mechanism.]